Inpatient burden of respiratory syncytial virus in children ≤2 years of age in Germany: A retrospective analysis of nationwide hospitalization data, 2019–2022

Abstract Background Respiratory syncytial virus (RSV) causes respiratory tract disease in seasonal waves, primarily in infants and young children. This study aims to quantify the number of RSV‐related hospitalizations in children ≤2 years of age and to determine corresponding resource use and costs in Germany. Methods We retrospectively analyzed population‐wide hospital data from the Institute for the Hospital Remuneration System (InEK) from 2019 to 2022. RSV cases were identified using the RSV‐specific 10th revision of the International Classification of Diseases (ICD‐10) codes J12.1, J20.5, and J21.0. The RSV‐associated proportion of all hospitalizations caused by severe acute respiratory infections (SARIs), clinical manifestations, length of stay (LOS), intensive care unit (ICU) admissions, ventilation rates, and hospitalization costs were retrieved. Results We identified 98,220 hospitalizations (26,052, 15,407, 31,362, and 25,399 in 2019, 2020, 2021, and 2022, respectively) with a principal RSV diagnosis in children aged ≤2 years in Germany. The majority of RSV hospitalizations (73,178) occurred in infants (<1 year), with annual incidence rates ranging from 14.9 to 28.6 per 1000 population. Fifty‐eight percent of all SARI hospitalizations in this age group were attributable to RSV. In children aged ≤2 years, mean LOS was 4.5 days, 6.1% of cases were admitted to ICU, and 5.3% of cases were ventilated. Mean hospitalization costs per case ranged from €3001 to €3961 over the study period. Conclusions RSV causes substantial disease burden and is a leading cause of SARI‐related hospital admissions of children ≤2 years of age in Germany. Our results confirm the need to explore and evaluate strategies to prevent RSV in infants and young children.


| BACKGROUND
5][6][7][8][9] Compared with influenza, RSV causes up to 16 times more hospital stays and emergency room visits in children younger than 5 years. 1 In a recently updated systematic review and meta-analysis on childhood disease burden of RSV-related LRTI, it was estimated that 33.0 million LRTI cases and 3.6 million LRTI hospital admissions were due to RSV in children aged 0-60 months globally in 2019. 10The same study estimated the incidence of RSV-related LRTI in high-income countries to be 38.5 per 1000 infants aged 0-12 months.0][11][12][13][14][15] A study in seven European countries showed that children born 2 months before the peak of the RSV season were more likely to be hospitalized due to RSV in the first year of life. 168][19] In addition to prematurity, chronic conditions, such as congenital heart disease (CHD), are associated with a more severe course of RSV infection. 20,21However, most children hospitalized for an RSV-related LRTI episode do not have a history of prematurity or underlying diseases. 1,5,11,22eatment options against severe RSV infections are limited and prevention remains the most promising strategy to reduce the burden of severe RSV disease. 23Until late 2023, passive immunization with palivizumab, a monoclonal antibody that needs to be administered monthly during the RSV season, was the only available pharmaceutical intervention to prevent severe RSV disease in at-risk infants.
Palivizumab is indicated for children being born prematurely with 35 weeks of gestational age or less, entering their first RSV season, or children <2 years of age with bronchopulmonary dysplasia (BPD) or hemodynamically significant CHD. 246][27] These new interventions aim to prevent severe RSV disease also in infants currently outside the population eligible to receive immunization with palivizumab.
To support the introduction of technologies such as monoclonal antibodies or maternal vaccines, data on the burden of RSV are essential.Evidence on the disease burden of RSV-associated inpatient stays and the associated resource utilization in young children in Germany is limited and often outdated.To date, there is no comprehensive nationwide analysis that covers all RSV hospitalizations in Germany.
This study aims to quantify the number of RSV-associated LRTI hospitalizations and to describe corresponding resource use and costs in children under 2 years of age from 2019 to 2022 in Germany.

| Data source
We retrospectively analyzed population-wide hospital data from the German Institute for the Hospital Remuneration System (InEK).
The case-related data are compulsory to be reported to InEK by every hospital in Germany and are accessible to the public for research purposes in anonymized form via an online data access tool.Data were extracted from the so-called § 21 datasets, which include information on all cases of hospitalization as required by law, that is, sections 1 and 3b of § 21 of the German Hospital Remuneration Act (KHEntgG). 28The data source allows identification and analysis of cases by principal and secondary diagnoses, pre-specified age groups, diagnosis-related groups (DRGs), discharge reason, LOS, ICU admissions, ventilation hours, and dates of admission and discharge.
The definition of ventilation in the data includes both invasive mechanical ventilation procedures and non-invasive respiratory support, following the German coding guideline published by InEK. 29e hospital discharge date determines the calendar year a case is assigned to.Due to data protection measures, subgroups with fewer than three cases cannot be investigated separately.

| Case definitions
RSV-associated hospitalization cases were defined using the 10th revision of the International Classification of Diseases (ICD-10), that is, the RSV-specific codes J12.1 (RSV pneumonia), J20.5 (acute bronchitis due to RSV), and J21.0 (acute bronchiolitis due to RSV), when coded as principal diagnosis at hospital discharge.Secondary diagnoses were not included to prevent double counting and to ensure that the analysis focuses on cases that were primarily RSV associated.
International studies have already explored broader case definitions for RSV to account for underreporting of RSV with its specific ICD-10 codes. 4,30,31Therefore, we also extracted all acute bronchiolitis diagnoses in order to quantify the RSV-specific proportion of bronchiolitis hospital stays.We used the ICD-10 codes J21.1 (acute bronchiolitis due to human metapneumovirus [hMPV]), J21.8 (acute bronchiolitis due to other specified organisms), and J21.9 (acute bronchiolitis, unspecified) in addition to J21.0 to determine the total number of hospitalizations associated with bronchiolitis and the distribution of bronchiolitis-causing pathogens.
We further calculated the proportion of RSV of hospitalizations associated with any severe acute respiratory infection (SARI).SARI was defined as hospitalization cases with a principal diagnosis of any ICD-10 code of J09-J22 (J09-J11: influenza, J12-J18: pneumonia, J20: acute bronchitis, J21: acute bronchiolitis, and J22: unspecified acute lower respiratory infection) at hospital discharge, following the approach of the Robert Koch Institute. 32

| Data extraction and analysis
All RSV-, bronchiolitis-, and SARI-related hospitalizations from 2019 to 2022 were extracted by age group (<1 year and 1-2 years) and by calendar year.The age groups were aggregated from the pre-defined age groups available in the database.Information on ICU admission, ventilation, mean LOS, in-hospital mortality, and the DRG distribution was extracted for all RSV cases.Hospitalization incidence per 1000 population was calculated using the population of the corresponding age groups on December 31 of the respective calendar year from the German Federal Statistics Office. 33If the combination of year and age group resulted in three or less fatal cases, we manually aggregated groups with cases from other age groups and calculated the difference to identify the exact number of in-hospital deaths by year and age group.The weekly number of RSV-associated hospitalizations was extracted by age group and by calendar week (CW) of hospital discharge to investigate seasonal patterns.All calculations were carried out in Microsoft Excel 365.

| Hospitalization cost calculations
We calculated hospitalization costs per case from a third-party payer perspective, covering the direct costs related to an inpatient stay.
For each year, we extracted frequency tables of DRGs that were allocated for RSV hospitalization cases.Due to data protection measures, DRGs allocated less than three times within the respective calendar year could not be considered.DRG distributions were stratified by age groups (<1 year, 1-2 years, and total ≤2 years) and by ICU admission status (total cases, ICU-admitted cases, and cases with normal ward stay only).
To calculate the costs per hospitalization case, we used the German federal base rates of €3544.97,€3679.62,€3747.98,and €3833.07 for 2019, 2020, 2021, and 2022, respectively. 34For each DRG allocated to RSV cases in 2019, the federal base rate was multiplied with the relative DRG weight. 35The weighted mean and standard deviation of all allocated DRG revenues were calculated to estimate the average costs of RSV hospitalizations.After a legal change in the German DRG system coming into effect from 2020, nursing care was phased out of the fixed-rate system.Therefore, RSV hospitalization costs from 2020 to 2022 were calculated as the sum of nursing care revenue (i.e., the mean LOS multiplied with the DRG-specific relative nursing care weight and the fixed daily nursing care valuation rate) and the federal base rate multiplied with the respective relative DRG weights. 36,37We applied the daily nursing care valuation rates of €146.55,€163.09, and €200.00 for 2020, 2021, and 2022, respectively. 38To calculate the total annual costs of RSV hospitalizations in Germany, we multiplied the number of cases with the mean costs per case.All costs are expressed in Euro (€) for the respective price year.

| RSV-associated hospitalizations
From 2019 to 2022, a total of 98,220 hospitalizations with a principal RSV diagnosis were identified in children ≤2 years of age (see Table 1 for details).The highest number of RSV-associated hospital stays occurred in 2021 (N = 31,362), followed by 2019 (N = 26,052), 2022 (N = 25,399), and 2020 (N = 15,407).In each of the four years, infants <1 year of age were more affected than children aged

| In-hospital mortality
Twenty-four deaths occurred in hospitalized children aged ≤2 years over the study period, translating into low case fatality rates between 0.01% and 0.04% from 2019 to 2022 (see Table 1).In the age group with the highest number of RSV-associated hospitalizations (children aged <1 year), case fatality ranged from 0.005% to 0.026% over the study period.

| Clinical manifestations
The distribution of RSV-specific principal diagnoses for children ≤2 years of age for each of the four years studied is displayed in Figure 3. Bronchiolitis (J21.0) was coded as a principal diagnosis in 49% of all RSV-associated hospital stays over the study period.

| Medical resource utilization and hospitalization costs
ICU admission rates varied with age and observation year (see Table 1).The ICU admission rate for under-1-year-olds was 6.6% and ranged from 5.3% to 8.0% over the 4-year study period.[41][42][43][44] Over the study period, the seasonality pattern of RSV hospitalizations from our data matches well with the seasonality of RSV activity   40 The seasonal peaks in the respective years in our analysis ranged between 1 and 3 weeks later, namely, in CW6 in 2019, CW7 in 2020, and CW43 in 2021, which is likely due to mixed effects of hospitalizations occurring with few days of delay after infections and our analysis being based on hospital discharge rather than hospital admission dates.For 2022, our analysis suggests seasonality comparable with the 2021-2022 season, with a slightly higher peak in CW49 in 2022.Overall, there were less RSV-associated hospitalizations in 2022 compared with 2021.
However, the condensed appearance of RSV hospitalizations and the simultaneous occurrence of influenza circulation in late 2022 might have put severe pressure on the health care system. 39study analyzing RSV hospitalizations of infants and young children in Germany in 2021 reported a proportion of 11.5% of hospitalized pediatric patients with RSV infection (age ≤ 5 years, 66% of included subjects <1 year) who received respiratory support, of which 10.2% received non-invasive support and 1.3% were mechanically ventilated. 43In contrast, our analysis provided a ventilation rate of 5.3% for children ≤2 years of age in the corresponding season in 2021.The considerable difference is likely attributable to the varying definitions of "ventilation" between the studies, as the hospitalization data we investigated are based on the German DRG system, in which both mechanical ventilation and respiratory support, such as continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC), are considered as ventilation in infants. 29 our knowledge, only one previous study estimated the costs associated with RSV hospitalizations of children in Germany. 45The study was built on data gathered from 1999 to 2001 and reported mean direct medical costs associated with RSV hospitalization of children aged ≤2 years of €2507.Assuming that the analysis was  three years fully or partially affected by the pandemic.Yet, our study has several limitations.First, we focused on ensuring good specificity when extracting RSV hospitalization cases from the database, potentially at the expense of sensitivity.We excluded cases with only secondary diagnoses of RSV-specific ICD-10 codes to avoid double counting and to exclude cases that were primarily hospitalized for other conditions.Therefore, we could not make use of the ICD-10 code B97.4 (RSV as the cause of diseases classified to other chapters).
We do not expect considerable underestimation of hospitalization incidence due to this approach, as we expect B97.4 to be primarily used in association with upper respiratory tract infections, which are less likely to be hospitalized.Further, we exclusively used RSV-specific ICD-10 codes to identify RSV hospitalizations, expecting that there was reliable routine testing for RSV in German hospitals for children aged ≤2 years.Had we taken into account the ICD-10 code J21.9 (acute bronchiolitis, unspecified), the RSV-associated hospitalization incidence in children aged ≤2 years would increase from 11.0 to 11.5, 6.6 to 6.9, 13.3 to 13.7, and 10.8 to 11.2 in 2019, 2020, 2021, and 2022, respectively.Previous studies have suggested to explore even wider RSV case definitions to ensure sensitivity, as the clinical practice of routine testing for RSV is associated with a high level of uncertainty and potentially underestimates RSV as the cause for hospitalization with SARI. 4,30,31,47Second, using hospitalization data, we were only able to quantify the inpatient burden of RSV.To get a full picture of the burden of medically attended RSV infections in Germany, outpatient treatment data are also relevant.A previous study estimated excess visits to primary care facilities in Germany due to RSV infections in the 2018-2019 season, reporting a total of 12,400 (95% confidence interval [CI] 10,400-14,600) excess visits in the age group of 0-1 years, underlining the substantial burden of RSV also in the outpatient setting. 48Third, our analysis was not able to differentiate between subgroups with certain risk factors or comorbidity profiles in hospitalized children.8][19] Last, by structuring the analysis by calendar years, it is possible that a calendar year includes cases of two epidemic seasons.However, as we reported weekly hospitalization cases over time for the full study period in Figure 2, the seasonality of RSV hospitalizations is captured and comparison with other studies is enabled.

| CONCLUSIONS
RSV causes substantial disease burden, and our study reinforces that RSV is a leading cause of SARI-associated hospital admissions in children ≤2 years of age in Germany.With progress in clinical development of new preventive measures which led to recent authorization of a long-acting monoclonal antibody for passive immunization of infants and a vaccine for maternal immunization, our results confirm the need to explore and evaluate strategies to prevent RSV in infants and young children.

Figure 2
Figure2shows the weekly number of RSV hospitalizations for all age groups (<1 year, 1-2 years, and total ≤2 years) over the 4-year study period.Seasonal peaks were reached in CW6 and CW7 of the 2018-2019 and 2019-2020 season, respectively.In contrast, there was no noticeable RSV activity in 2020-2021, followed by a premature 2021-2022 season with a peak in CW43 in 2021.In late 2022, a seasonal peak was reached in CW49.

F I G U R E 3
Principal diagnoses of respiratory syncytial virus (RSV) hospitalizations in children ≤2 years of age, by age group and year, Germany 2019-2022.described for Germany in scientific literature.A study determining epidemic seasons in Germany using RSV positivity rates reported seasonal peaks in CW3 for the 2018-2019 season, in CW6 during the 2019-2020 season, no 2020-2021 season, and a peak in CW41 in 2021 for the early onset 2021-2022 season.
conducted in 2004 (1 year prior to publication) and taking into account the years of inflation by adjusting this cost value with the German consumer price index from the German Federal Statistics Office, 46 the result corresponds to €3443 at 2022 price level.This fits well to our reported range of mean hospitalization costs from €3001 to €3961 from 2019 to 2022, especially considering that the German DRG system was not implemented during the data collection period of the study by Ehlken et al., and their analysis was based on the previous German per diem payment hospital reimbursement system.Incidence rates of hospital admissions with RSV-related respiratory infections in six European countries (Denmark, England, Finland, Norway, the Netherlands, and Scotland) were recently estimated in a study for the years 2006-2018 using a retrospective registry and population-based modeling approach.
Hospitalization incidence, health care resource use, and case fatality associated with RSV hospitalizations in children ≤2 years of age by year, Germany 2019-2022.-2years,accountingfor 72%-78% of all RSV hospitalizations in children aged ≤2 years.This corresponds to an infant hospitalization incidence of 26.2, 14.9, 28.6, and 25.5 per 1000 population in 2019, 2020, 2021, and 2022, respectively.In children aged 1-2 years, incidence ranged from 2.5 to 5.6 per 1000 population.During the study period, 58% of all SARI hospitalizations in the age group of <1 year had a principal RSV diagnosis.In the age group from 1 to 2 years, this proportion decreased to 20%.The proportions of RSV among all SARI hospitalizations in children ≤2 years of age for each year are presented in Figure1.